Abstract Acute injury of the gut mucosa occurs commonly in patients with critical surgical events such as trauma, thermal injury, shock, and massive surgical operations. Because the exact mechanisms underlying gut mucosal injury/repair remain largely unknown, effective therapies to preserve the epithelial integrity in patients with critical surgical illness are limited, leading to acute massive hemorrhage, epithelial barrier dysfunction, sepsis, and in some instances multiple organ dysfunction syndrome and death. Recently, circular RNAs (circRNAs) have drawn increasing interest due to their prevalence and range of potential biological functions by interacting with microRNAs (miRNAs) and RNA-binding proteins (RBPs). In preliminary studies, our genome-wide circRNA expression profiles reveal that ~300 circRNAs from total 9360, including Cdr1as and circHIPK3, which were differentially expressed between injured mucosa induced by septic stress vs uninjured mucosa from control mice. Ectopically expressed Cdr1as inhibited intestinal epithelial repair after wounding, whereas circHIPK3 promoted intestinal epithelial regeneration. Cdr1as and circHIPK3 were also found to interact with several miRNAs such as miR-7 and miR-29b. Based on these exciting observations, we advance a paradigm-shifting hypothesis that circRNAs Cdr1as and circHIPK3 play an important role in intestinal mucosal repair by interacting with given miRNAs after acute injury under critical surgical conditions. Three specific aims are proposed to test the hypothesis: 1) To define the exact roles of Cdr1as and circHIPK3 in the regulation of intestinal mucosal repair after acute injury induced by surgical stress; 2) To identify novel target miRNAs of Cdr1as and circHIPK3 that are important for intestinal mucosal repair after acute injury; and 3) To characterize the mechanism by which cellular abundances of Cdr1as and circHIPK3 are regulated in response to critical surgical stress. Completion of these experiments will make a significant conceptual advance by linking the circRNA/miRNA interaction with gut mucosal repair after acute injury in patients with critical surgical illnesses. The unique cellular stability and capacity of circRNAs to interact with miRNAs and RBPs will also place circRNAs as promising targets or as therapeutic vectors for developing new treatment to maintain gut epithelial integrity or/and enhance mucosal repair after injury in surgical clinical setting.